The invention is concerned with a pharmaceutical preparation for subcutaneous, parenteral administration, which contains bisphosphonic acids or their salts as the active substance, as well as the production of this preparation. By means of the preparation in accordance with the invention it is possible to administer locally relatively high concentrations of bis-phosphonates without the occurrence of incompatibilities.
Bisphosphonates and their salts have been in use for years as highly effective medicaments for the treatment of various disorders of bone metabolism. Thus, a variety of bisphosphonates are used for the treatment of hypercalcaemia, malignant bone growth disorders (metastatic bone disease) as well as osteoporosis, while others are in clinical development. Clodronate, ibandronate, tiludronate, etidronate, alendronate, risedronate, zoledronate among others can be named as examples. Bisphosphonates are used in a broad dosage range taking into consideration the widest variety of factors, especially the medical indication. Thus, parenteral preparations for intravenous infusion and injection are preferably made available and utilized.
The subcutaneous, parenteral administration of clinically relevant amounts of bisphosphonic acids or their salts is, however, problematic. Inflammations, pains and necroses occur when bisphosphonate solutions are administered subcutaneously in therapeutically relevant concentrations, which are, for example, well tolerated in the case of intravenous administration. Of course, the subcutaneous administration is especially attractive in many respects, because this mode of administration is perceived by the majority of patients to be much more pleasant than intravenous administration. It can be performed by medical auxiliaries or by patients themselves.
The pharmacokinetic differences which can occur in the case of subcutaneous administration vis-à-vis intravenous administration are not of significance for the fields of indication osteoporosis and osteoporosis prophylaxis which are at the centre of interest, since bis-phosphonates display their activity after binding to bones, are accumulated there for a very long time and therefore their residence times in the blood after injection or also after oral administration are only of secondary importance.
Thus, only a few, not completely satisfactory proposals for the development of subcutaneously usable bisphosphonate preparations have hitherto become known.
Difficulty soluble zinc and magnesium salts of 1,1-bisphosphonic acids are described in DE 42 44 422 A1, with the object of releasing therapeutically relevant amounts of active substance slowly by dissolution from a local depot.
However, for various reasons this principle is not well suited to achieve a significantly improved compatibility. Thus, even if the dissolution kinetic is altered a good compatibility does not, however, result, since a particulate system is formed by the difficultly soluble salt. It has been established that this not only has numerous disadvantages upon administration, but also leads to additional difficulties. From the technological viewpoint not only the production, dosing and decantation, but also the storage, quality control and quality guarantee of such systems is very difficult. Particulate systems are mainly suspensions which are physically unstable and, for this reason, in the case of short-term storage already undergo changes which are relevant to quality. As mentioned above, the administration of such particulate systems is not simple. Thus, dosing problems, which are caused by phase separation or sedimentation, can occur immediately upon administration. The obstruction of injection needles by suspension particles is likewise a problem which has to be taken into consideration seriously.
The subcutaneous administration of difficultly soluble particles is not optimal also from the toxicological viewpoint. The presence of foreign particles induces specific and non-specific defence mechanisms which lead to diverse reactions, especially to local cellular changes. Phagocytes accumulate, other cells accompany the degradation and an encapsulation of the foreign particles may occur. In summary, particulate systems lead to generally undesired reactions which decrease compatibility.
On the other hand, water-soluble calcium salts of ibandronate for the production of medicaments are described in DE 42 44 423 A1. These eliminate the disadvantages of difficultly soluble salts and, on the basis of a lower solubility than the usual alkali or ammonium salts, they should have a better tissue compatibility than these without exhibiting the disadvantages of the suspensions.
This formulation strategy is, however, not completely conclusive and in practice does not lead to the desired, medically relevant improvement in compatibility. As a molecular dispersed solution (xe2x80x9ctrue solutionxe2x80x9d in the physico-chemical sense) is present, then its concentration of dissolved active substance (e.g. 1 mg/ml) alone determines the compatibility and not on the other hand the saturation solubility. While the saturation solubilities of e.g. Na+ and Ca2+ salts of bisphosphonates, especially ibandronate, differ significantly, their individual physiological irritating effects are on the other hand the same in the case of the same dissolved concentration.
It has been established that the achievable compatibility limits or active substance concentrations of water-soluble Ca2+ salts, which are well tolerated after subcutaneous administration, are so low that they are not usable in practice. In particular, the treatment interval of only one or a few injections every three months, which is especially desirable and attractive from the viewpoint of patients and of medical personnel, can therefore not be realized.
The underlying purpose of the invention accordingly lay in the provision of pharmaceutical preparations suitable for subcutaneous administration which contain bisphosphonic acids or their physiologically compatible salts and with which it is possible to administer locally high, therapeutically relevant concentrations of bisphosphonates compatibly such that medically significant treatment regimens with administrations at long time intervals (xe2x89xa74 weeks) are possible.
The problem of the invention is solved by an aqueous pharmaceutical preparation which contains the active substance or the active substance mixture and at least one compound which inhibits a diffusion of the active substance in the tissue, with the active substance being present in dissolved form in the preparation and the active substance and diffusion-inhibiting compound being selected such that the pharmaceutical preparation contains no solid particulate components. If desired, other usual pharmaceutical carriers and/or adjuvants, which, however, should not form particles, are present in the preparation.
The invention is concerned with a pharmaceutical preparation for subcutaneous, parenteral administration, which contains bisphosphonic acids or their salts as the active substance, as well as the production of this preparation. By means of the preparation in accordance with the invention it is possible to administer locally relatively high concentrations of bis-phosphonates without the occurrence of incompatibilities. The pharmaceutical composition of this invention comprises an aqueous gel having a viscosity of xe2x89xa7220 mPa*s containing as an active ingredient for combating osteoporosis a bisphosphonate acid or its pharmaceutically acceptable salt dissolved in aqueous solution and a polymeric gel forming agent capable of inhibiting diffusion of the active ingredient with human tissue. This composition is in a dosage form for subcutaneous administration.
In a preferred embodiment the present invention comprises a gel-like, aqueous pharmaceutical preparation for subcutaneous administration containing bisphosphonic acids or their physiologically acceptable salts, characterized in that the pharmaceutical preparation contains at least one compound which inhibits the diffusion of the active substance in the tissue, with the active substance being present in dissolved form in the preparation and the preparation having a viscosity xe2x89xa7220 mPa*s.
In accordance with a preferred embodiment of this invention, the pharmaceutical composition comprises an aqueous gel having a viscosity of xe2x89xa7220 mPa*s in a unit dosage form suitable for subcutaneous administration to the tissue of human patients, said gel containing as an active ingredient 200-1000 xcexcg, preferably 200-300 xcexcg, of a bisphosphonate acid or its pharmaceutically acceptable salt, which are active in combating osteoporosis dissolved in an aqueous solution, and from about 0.01%-15% by weight based upon the weight of the aqueous gel, of a polymeric gel forming agent capable of inhibiting diffusion with human tissue. In accordance with another embodiment of this invention, the composition contains 200-1000 xcexcg, preferably 200-300 xcexcg of the active substance or active substance mixture, 0.5 mg of a calcium salt and 15 mg of a cellulose derivative or alginate in 1 ml of water. In accordance with still another embodiment of this invention, the composition contains 1 mg of the active substance or active substance mixture, 1 mg of a calcium salt and 50 mg of a cellulose derivative or alginate in 1 ml of water.
This invention also includes a method for combating osteoporosis by subcutaneous administering to the tissue of a human patient an aqueous gel having a viscosity of xe2x89xa7220 Pa*s containing as an active ingredient a bisphosphonate acid or its pharmaceutically acceptable salt active in combating osteoporosis dissolved in an aqueous solution and present in said gel in an effective amount to combat osteoporosis and a polymeric gel forming agent capable of inhibiting diffusion of said active ingredient into human tissue. The invention also includes a method for subcutaneous administration of osteoporosis bisphosphonates combating agent by utilizing the compositions of this invention.
The addition of the diffusion-inhibiting substance prevents on the basis of specific and non-specific interactions with the active substance and its counter-ions (such as e.g. Na+, Ca2+ etc.) the bisphosphonic acids or their salts from causing incompatibility symptoms, such as e.g. irritations, in the tissue after subcutaneous administration.
The diffusion-inhibiting substances are in the meaning of the invention preferably hydrogel-forming substances and other non-particulate matrices, preferably natural and synthetic polymers.
In accordance with the invention any conventional pharmaceutically or physiologically acceptable polymer and gel forming agents can be utilized to produce the aqueous gels of this invention. These gel forming agents will inhibit the diffusion of the active ingredient with human tissue when the composition is administered to a human patient subcutaneously. These conventional polymeric gel forming agents include cellulose derivatives, alginic acid derivatives, dextrans, hyaluronic acids, dermatan and heparan sulphates, gelatins, collagen, polyvinylpyrrolidone, polyvinyl alcohol, poly(meth)acrylic acids, poly(meth)acrylates and/or their derivatives. Derivatives are chemically modified entities obtained by amidation, alkylation, carboxymethylation, addition of fatty acid units or addition of polyethyleneglycol-units (so called xe2x80x98pegylationxe2x80x99). To get the necessary gel forming properties the polymers additionally may be cross-linked by e.g. glutardialdehyde. In case of acidic compounds (alginic acid, polymethacrylates) derivatives are also their salts (such as ammonium-, barium-, magnesium-, calcium-salt). These compounds are known in the art and described for example in Ash, M. and I.: Handbook of Pharmaceutical Additives. Gower, 1995, 887f.; 915-918; Fiedler, H. P.: Lexikon der Hilfsstoffe. ecv, 1998; Kibbe, A. H.: Handbook of Pharmaceutical Excipients. 3rd ed., Pharmaceutical Press, 2000. Preferably, the natural polymer is selected from the group consisting of cellulose derivatives, alginic acid derivatives, dextrans, gelatines, collagen, hyaluronic acids and/or dermatan and heparan sulphates. The cellulose derivatives are the preferred diffusion-inhibiting substances in the meaning of the invention. In the case of the cellulose derivatives there preferably come into consideration the soluble alkyl- or hydroxyalkylcellulose derivatives, such as e.g. hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), methylhydroxyethylcellulose (MHEC), hydroxypropylmethylcellulose (HPMC), carboxymethylcelluose (CMC), methylcellulose (MC) or their mixtures.
The term xe2x80x9calkylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain alkyl group containing a maximum of 7, preferably a maximum of 4, carbon atoms, e.g., methyl, ethyl, n-propyl, 2-methylpropyl (iso-butyl), 1-methylethyl (iso-propyl), n-butyl, and 1,1-dimethylethyl (t-butyl), preferably methyl and ethyl.
A more preferred natural polymer is sodium carboxymethylcellulose. Another preferred natural polymer is alginate.
In another preferred embodiment of the present invention, the synthetic polymer is selected from the group consisting of poly(meth)acrylic acids, poly(meth)acrylates, polyvinylpyrrolidone and polyvinyl alcohol.
In accordance with the invention the gel formers are used in concentrations which produce the viscosities which on the one hand produce the requisite diffusion inhibition and on the other hand permit the requisite injectability to human subjects. The gel former is used in concentrations of from 0.01 to 15% (w/w).
In an especially preferred embodiment of the invention sodium carboxymethylcellulose (Na CMC) is used in a concentration of from 1 to 7% (w/w), particularly of 4-6% (w/w). In another preferred embodiment alginate is used in concentrations of from 1 to 5% (w/w), especially of from 2 to 3% (w/w).
In accordance with the invention the preferred viscosities of the thickened preparations produced by means of the gel former lie in the range of xe2x89xa7220 mPa*s, particularly of 350 to 1800 mPa*s, whereby the preparations must be administerable by means of suitable injection needles.
In a further especially preferred embodiment, calcium salts are added to the composition to produce calcium ions (final concentration of from 1 to 20 mM, preferably from 5 to 15 mM), with these being preferably added in the form of calcium chloride.
Bisphosphonic acids are well known for combating osteoporosis. These not only include bisphosphonic acids but their pharmaceutically acceptabel salts and esters. These compounds and their method of administration for combating osteoporosis have been described throughout the literature. However, there has not been described an effective means for subcutaneously administering these antiosteroporosis active bisphosphonic acids, salts and esters to human patients. The composition of this invention in its aqueous gel form provides a means and method for subcutaneously administering these compositions subcutaneously to human patients. By combating osteoporosis, these phosphonates are useful both in the prophylaxis and treatment of osteoporosis.
Also, this invention provides a new method for subcutaneously administering these antiosteoporosis bisphosphonates to patients through subcutaneous means. In accordance with this invention, any of the conventional antiosteoporosis active bisphosphnates can be administered subcutaneously through use of the compositions of this invention so as to combat osteoporosis.
Bisphosphonic acids or their physiologically acceptable salts as pharmaceutical active substances are described for example in U.S. Pat. No. 4,666,895, U.S. Pat. No. 4,719,203, EP-A-252,504, EP-A-252,505, U.S. Pat. Nos. 4,777,163, 5,002,937, and U.S. Pat. No. 4,971,958. Methods for the preparation of bisphosphonic acids may be found in, e.g., U.S. Pat. Nos. 3,962,432; 4,054,598; 4,267,108; 4,327,039; 4,407,761; 4,621,077; 4,624,947; 4,746,654; 4,922,077; 4,970,335; 5,019,651; 4,761,406; and U.S. Pat. No. 4,876,248; J. Org. Chem. 32,4111 (1967) and EP-A-252,504.
The pharmaceutically acceptable salts of bisphosphonic acids may also be employed in the instant invention. Examples of base salts of bisphosphonic acids include ammonium salts, alkali metal salts such as potassium and sodium (including mono, di- and tri-sodium) salts (which are preferred), alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. The non-toxic, physiologically acceptable salts are preferred. The salts may be prepared by methods known in the art, such as described in European Patent Pub. No. 252,504 or in U.S. Pat. No. 4,922,077.
In a preferred embodiment of the present invention, the term xe2x80x9cbisphosphonatexe2x80x9d of the present invention corresponds to compounds of general formula 
wherein A and X are independently selected from the group consisting of hydrogen, hydroxy, halogen, amino, SH, phenyl, alkyl, mono- or dialkylamino, mono- or dialkylaminoalkyl, alkoxy, thioalkyl, thiophenyl, and aryl or heteroaryl moieties selected from the group consisting of phenyl, pyridyl, furanyl, pyrrolidinyl, imidazolyl, and benzyl, wherein the aryl or heteroaryl moiety is optionally substituted with alkyl.
In the foregoing chemical formula, A can include X and X include A such that the two moieties can form part of the same cyclic structure.
The foregoing chemical formula is also intended to encompass carbocyclic, aromatic and heteroaromatic structures for the A and/or X substituents, e.g. naphthyl, quinolyl, isoquinolyl, adamantyl, and chlorophenylthio.
Preferred structures are those in which A is selected from the group consisting of hydrogen, hydroxy, and halogen, an X is selected from the group consisting of alkyl, halogen, thiophenyl, thioalkyl and dialkylaminoalkyl.
More preferred structures are those in which A is selected from the group consisting of hydrogen, hydroxy, and Cl and X is selected from the group consisting of alkyl, Cl, chlorophenylthio and dialkylaminoalkyl.
Most preferred is when A is hydroxy and X is (N-methyl-N-pentyl)amino-ethyl, i.e. ibandronate.
Examples of bisphosphonates, i.e. bisphosphonic acids and pharmaceutically acceptable salts thereof which may be employed as active ingredients in the compositions and methods for subcutaneously administering these compositions of the instant invention:
a) 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (alendronate),
b) N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid,
c) 4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bis-phosphonic acid,
d) 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (pamidronate),
e) 3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid (ibandronic acid),
f) [3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid, monosodium salt, monohydrate] (ibandronate),
g) 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisposphonic acid,
h) 1-hydroxy-2-[3-pyridinyl]ethylidene-1,1-bisphosphonic acid (risedronate),
i) 4-(hyroxymethylene-1,1-bisphosphonic acid)piperidine,
j) cycloheptylaminomethylene-1,1-bisposphonic acid (cimadronate),
k) 1,1-dichloromethylene-1,1-diphosphonic acid and the dissodium salt (clodronate),
l) 1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1,1-bisphosphonic acid (EB-1053),
m) 1-hydroxyethane-1,1-diphosphonic acid (etidronic acid),
n) 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (neridronate),
o) 3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid (olpadronate),
p) [2-(2-pyridinyl)ethylidene]-1,1-bisphosphonic acid (piridronate),
q) (4-chlorophenyl)thiomethane-1,1-diphosponic acid (tiludronate),
r) 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid (zolendronate).
s) [(cycloheptylamino)-methylene]-bisphosphonic acid (icadronate), and/or
t) [1-Hydroxy-2imidazo-(1,2-a) pyridin-3-ylethylidene]-bisphosphonic acid
and pharmaceutically acceptable salts thereof.
Active substances used in accordance with the invention are aminobisphosphonates, such as e.g. ibandronate, clodronate, etidronate, risedronate, zoledronate, tiludronate, pamidronate, cimadronate (YM175) and/or alendronate or their sodium or calcium salts.
The active substances are preferably used in the form of their soluble salts to which belong ammonium salts, alkali and alkaline earth salts such as sodium, potassium, calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts or salts with amino acids such as e.g. arginine or lysine. It is especially preferred to use the sodium or calcium salts.
In a more preferred embodiment of the present invention, the bisphosphonate is 3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid (ibandronic acid) or pharmaceutically acceptable salts thereof, or even more preferably 3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid, monosodium salt, monohydrate.
In a preferred embodiment of the invention the preparation may comprise an active substance, a calcium salt and a diffusion inhibiting compound selected from the group consisting of carboxymethylcellulose and alginate.
In a preferred embodiment of the present invention a preparation as described above may contain 200-1000 xcexcg, preferably 200-300 xcexcg of the active substance or active substance mixture, 0.5 mg of a calcium salt and 15 mg of a cellulose derivative or alginate in 1 ml of water. Another preferred embodiment of the present invention may comprise 1 mg of the active substance or active substance mixture, 1 mg of a calcium salt and 50 mg of a cellulose derivative or alginate in 1 ml of water.
Another aspect of the present invention relates to a process for the production of an aqueous pharmaceutical preparation for subcutaneous administration containing bisphosphonic acids or their physiologically acceptable salts as the active substance as described above, characterized by dissolving the active substance in water and subsequently adding to the solution a compound which inhibits the diffusion in the tissue or mixing the active substance and diffusion-inhibiting compound and dissolving them together in water or adding the active substance to aqueous solutions of the diffusion-inhibiting compounds. Optionally a calcium salt is added.
The invention also refers to the use of a preparation as described above for the preparation of a medicament of the treatment of osteoporosis.
The production of the pharmaceutical preparations is carried out according to conventional procedures. For example, aqueous solutions of the active substance, optionally with the addition of a calcium compound, are produced and are then treated with the diffusion-inhibiting substance so that no solid particles are present or the active substance and diffusion-inhibiting compound, optionally with the addition of a calcium compound, are admixed, and dissolved together. In a further procedural variant, aqueous solutions of the diffusion-inhibiting substances are firstly produced and to these are subsequently added the active substances, optionally with the addition of a calcium compound.
By means of the thus-produced pharmaceutical preparations it is possible to utilize bisphosphonic acids or their salts subcutaneously in a pain-free and medically-safe manner.
Thus, e.g. by means of the preparations in accordance with the invention 1 mg of an active substance can be administered not only at intervals of 3 months or in appropriate aliquots every four weeks, but also in substantially smaller amounts every second, third, etc. day. In a particularly preferred embodiment 200-300 xcexcg of active substance or active substance mixture, optionally with the addition of calcium ions (7-12 mM) can be mixed with 15 mg of a diffusion-inhibiting substance, e.g. sodium carboxymethycellulose or alginate, and administered subcutaneously every 4 weeks. In another particularly preferred embodiment 1 mg of active substance or active substance mixture, optionally with the addition of 7 mM of calcium ions, is mixed with 50 mg of a diffusion-inhibiting substance, e.g. sodium carboxymethycellulose or alginate, and administered subcutaneously at intervals of 3 months. The pharmaceutical preparation can also be administered intermittently. Thus, a three-fold administration at intervals of 4 weeks can follow a pause of 3 months.
Accordingly, by means of the preparation in accordance with the invention highly concentrated doses are possible which are well tolerated after subcutaneous administration.
Furthermore, it is possible to provide the preparation in accordance with the invention so that it can be given using a multi-dose administration system (so-called pen) over a period of e.g. 4 to 6 weeks in prescribed intervals and dosages. Thereby, on pressing the button the appropriate dosage is injected once weekly in a manner which is especially simple and convenient for patients. With this, injection volumes between 25 xcexcg and 1 ml per injection can be realized.
In accordance with the invention it is also possible to administer locally relatively high concentrations of bisphosphonates without the need to make allowances for the disadvantages resulting in the use of highly concentrated solutions or particulate systems.
The invention is illustrated in more detain in the following Examples.